tbuckley/cabot-search huggingface dataset:
Abstract 10925: A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Prolonged Relaxation in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes With Hypertrophic Cardiomyopathy
Authors: Joona Valtonen, Katriina Aalto-Setala
Journal: Circulation (2022)

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases primarily caused by mutations in sarcomeric genes. However, HCM is also associated with mutations in non-sarcomeric proteins and a Finnish founder mutation for HCM in non-sarcomeric protein junctophilin-2 (JPH2) has been identified. MYK-461 is a recently described mechanistically novel small molecule that acts at the sarcomere to specifically inhibit contractility that has been proposed as a treatment for HCM. Here, we use MYK-461 to test whether direct reduction in contractility is sufficient to relieve phenotypic characteristics in human-induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) carrying JPH2 mutation T161K. Hypothesis: Currently all HCM patients are treated the same regardless of the underlying genetic defect. Current medication does not prevent or stop the thickening of the heart muscle; only the symptoms and arrhythmias can be controlled with beta-blockers or calcium blockers. MYK-461 decreases adenosine triphosphatase activity of the cardiac myosin heavy chain to reduce contractility, thus modifying the characteristic pathology of HCM. Methods: Skin fibroblasts from a Finnish patient with HCM causing JPH2 p.(Thr161Lys) were reprogrammed into hiPSCs and further differentiated into CMs. As a control line, an isogenic counterpart was generated using the CRISPR/Cas9 genome editing method. We evaluated the effect of MYK-461 treatment to T161K-hiPSC-CMs by their functional characteristics associated with JPH2 mutation. Results: By video microscopy, we identified increased contractility (BPM; 41±6 SEM, n=9) and prolonged diastolic phase (ms; 394.8±29.7 SEM, n=9) in T161K-hiPSC-CMs. Treatment with MYK-461 reduced contractility (BPM; 36±3 SEM, n=10) and relaxation phase (ms; 293.1±33.6 SEM, n=10) in a dose-dependent manner, displaying functional characteristics closer to isogenic-hiPSC-CMs control group. Conclusions: In conclusion, the results demonstrate that acute reduction in contractility is sufficient to relieve prolonged relaxation. Further, these studies suggest that T161K-hiPSC-CMs provide adequate in vitro platform for modelling the functional effect of MYK-461.
Abstract 10368: Optimal Medical Therapy After Percutaneous Coronary Intervention in Very Elderly Patients With Coronary Artery Disease
Authors: Takamitsu Nakamura, Takeo Horikoshi, Tsuyoshi Kobayashi, Toru Yoshizaki, Manabu Uematsu, Yousuke Watanabe, Akira Sato
Journal: Circulation (2022)

Introduction: It is still unclear whether optimal medical therapy (OMT) after percutaneous coronary intervention (PCI) has beneficial effects on long-term clinical outcomes in patients aged ≥80 years with coronary artery disease (CAD). Methods: This study analyzed the time to the first major adverse clinical event, namely, death or nonfatal myocardial infarction (MI), for up to 3 years after PCI using multicenter registry data. Data for 1056 patients aged &gt; 80 years with CAD who were successfully treated with PCI were included in the analysis. OMT was defined as a combination of an antiplatelet drug, a statin, a beta-blocker, and an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker. Results: In total, 204 (19%) patients in this study received OMT and 852 (81%) received sub-OMT. During a median follow-up of 725 days, adverse clinical events occurred in 183 patients (death, n=177; nonfatal MI, n=6). Kaplan-Meier analysis showed that patients who received OMT had a lower probability of adverse clinical events than those who received sub-OMT (p&lt;0.01, log-rank test). Propensity score matching yielded 202 patient-pairs treated with OMT or sub-OMT, in whom 64 adverse clinical events (death, n=59, nonfatal MI, n=5) occurred during follow-up. Kaplan-Meier analysis showed that patients who received OMT still had a lower probability of adverse clinical events than those who received sub-OMT (p=0.02, log-rank test). OMT remained significant in terms of reduction of the risk of adverse clinical events in a multivariate Cox proportional hazards model (hazard ratio 0.44; 95% confidence interval 0.26-0.75; p=0.003). Conclusions: OMT after PCI was associated with significantly fewer adverse clinical events, including all-cause death and nonfatal MI, in patients aged ≥ 80 years with CAD. OMT might be safe and effective for these very elderly patients.
Abstract 10284: Alcohol Consumption and Cardiovascular Outcomes in Patients With Atrial Fibrillation; a RE-LY AF Registry Analysis
Authors: Alireza Oraii, Faith Kirabo, Kumar Balasubramanian, Alexander P Benz, Jorge A Wong, William F McIntyre, David Conen, Jeff S Healey
Journal: Circulation (2022)

Introduction: The role of alcohol intake in patients with atrial fibrillation (AF) has been long debated. We aim to assess the association between different alcohol intake levels and cardiovascular outcomes in patients with AF. Methods: We performed a cross-sectional analysis of the RE-LY AF registry, which included 15,400 AF patients who visited emergency departments across 46 countries and were followed for one year after the baseline visit. Alcohol intake level was retrospectively ascertained and categorized into abstainers, light (&lt;7 standard drinks [SD]/week), moderate (7-13 SD/week), and heavy drinkers (≥14 SD/week) based on self-reported intake levels. The outcomes of interest were stroke/systemic embolism, heart failure (HF) hospitalization, all-cause mortality, and major bleeding events. Logistic mixed-effects regression models adjusted for baseline covariates were used to calculate the adjusted odds ratios (aOR) and 95% confidence intervals (CI). Results: A total of 14,058 AF patients (mean age: 65.9 years; 48% women) with available data on alcohol intake level were included. The odds of stroke/systemic embolism were not significantly increased in light (aOR 0.87, 95% CI: 0.60-1.26), moderate (aOR 0.92, 95% CI: 0.54-1.58), nor heavy drinkers (aOR 0.76, 95% CI: 0.39-1.49) compared to abstainers. Light and moderate drinking, compared to alcohol abstinence, were associated with reduced odds of HF hospitalization (light: aOR 0.75, 95% CI: 0.59-0.95; moderate: aOR 0.57, 95% CI: 0.38-0.85) and all-cause mortality (light: aOR 0.42, 95% CI: 0.30-0.58; moderate: aOR 0.42, 95% CI: 0.26-0.68; heavy: aOR 0.58, 95% CI: 0.35-0.97). Alcohol consumption was not associated with an excess risk of major bleeding events. Conclusion: As compared to non-drinkers, light and moderate alcohol drinking in patients with AF are associated with a lower risk of mortality and HF hospitalization, with no difference in thromboembolic and bleeding risk.
Abstract 10559: Causes of Early Mortality After Transvenous Lead Removal
Authors: Min Choon Tan, Justin Z Lee, Abhishek Deshmukh, Dan Sorajja, Arturo M Valverde, Komandoor Srivathsan, Luis Scott, Fred Kusumoto, Paul Friedman, Samuel Asirvatham, Siva K Mulpuru, Yong-Mei Cha
Journal: Circulation (2022)

Background: Recognition of the causes of early mortality after transvenous lead removal (TLR) is an essential step for the development of quality improvement programs. Objective: This study sought to determine the causes of early mortality after TLR and to further understand the circumstances surrounding death after TLR. Methods: We performed a retrospective analysis of all patients undergoing TLR from January 1, 2001, to January 1, 2021 at the Mayo Clinic (Rochester, Phoenix, and Jacksonville). Causes of death were identified through a detailed chart review of the electronic health record from within the Mayo Clinic system and outside records when available. The causes of death were further characterized based on whether it was related to the TLR procedure. Results: A total of 2,319 patients were included in the study. The overall 30-day all-cause mortality rate was 3%. Among all 30-day deaths, infection was the most common primary cause of death (42%). This was followed by decompensated heart failure (17%), procedure-related death (10%), sudden cardiac arrest (7%), and respiratory failure (6%). The 30-day mortality rate directly due to complications associated with the TLR procedure was 0.3% due to vascular tear and cardiac perforation. A third of deaths (33%) occurred after discharge from index hospitalization, among which 43% were readmitted before their death, 35% died at home or a nursing facility, and 22% were discharged on comfort care and died in hospice. The main reasons for readmission prior to death were sepsis and decompensated heart failure. Conclusions: The majority (90%) of 30-day mortality after TLR was not due to complications associated with TLR procedures. The primary causes were infection and decompensated heart failure. This highlights the importance of further research to reduce postoperative mortality from these factors, including deaths after hospital discharge.
Abstract 10664: Association of Unfavorable Social Determinants of Health With Stroke/TIA and Vascular Risk Factors: Results From the Hispanic Community Health Study/Study of Latinos
Authors: Gabriela Trifan, Linda Gallo, melissa lamar, Olga Garcia, Krista Perreira, Amber Pirzada, Gregory A Talavera, Sylvia W Wassertheil-Smoller, Carmen Isasi, Jianwen Cai, Martha L Daviglus, Fernando Testai
Journal: Circulation (2022)

Introduction: Social Determinants of Health (SDOH) contribute to the development of diseases and disproportionally affect minoritized groups. There is a paucity of information describing the relationship between SDOH, stroke/TIA and vascular risk factors (VRFs) in Hispanics/Latinos. Hypothesis: Unfavorable SDOH are associated with self-reported stroke/TIA and with increased VRFs. Methods: Cross-sectional data from cohort study of Hispanic Community Health Study/Study of Latinos (2014-2017). SDOH were assessed using questionnaires and previously validated scales. VRFs were hypertension, diabetes mellitus, hypercholesterolemia, smoking, at-risk alcohol use, and obesity. We investigated the association between the SDOH (individually and as count) and stroke/TIA using weighted complex survey multivariable logistic and linear regression analyses. Results: For individuals with stroke/TIA (weighted n=388), the mean age (58.9, 95% CI=56.4-61.5) differed from those without stroke/TIA (weighted n=11,210; 46.8, 95% CI=46.3-47.4). In bivariate analysis, income &lt;$20,000, education less than high school, no health insurance, perceived discrimination, not retired and not currently employed, upper tertile for chronic stress, and lower tertiles for social support and language- and social-based acculturation were associated with stroke/TIA and used in further analysis. Participants were grouped into 5 categories based on the distribution of SDOH (≤1, 2, 3, 4 and ≥5 SDOH). Increasing number of SDOH was directly associated with the odds of each individual VRFs investigated (except for at-risk alcohol) and VRF count (β=0.11, 95% CI=0.09-0.14). After adjustment for confounders, the odds of stroke/TIA increased 2.3 times in individuals with three SDOH (95% CI 1.6-3.2) and 2.7 times (95% CI 1.9-3.7) for those with ≥5 SDOH, compared to those with ≤1 SDOH. In final model, income, discrimination, social support, chronic stress, and employment status were individually associated with higher odds of stroke/TIA. Conclusions: Increased number of SDOH increased odds for stroke/TIA and VRFs. The association between SDOH and stroke/TIA remained significant after adjustment for VRFs, suggesting the participation of additional mechanisms of disease.
Abstract 10744: Predictive Value of Calcium Volume Measurement Determined by Computed Tomography for Paravalvular Leakage After Transcatheter Aortic Valve Implantation
Authors: Daisuke Isomatsu, Akihiko Sato, Yuki Muto, Satoshi Abe, Tomofumi Misaka, Masayoshi Oikawa, ATSUSHI KOBAYASHI, Akiomi Yoshihisa, Kazuhiko Nakazato, Takafumi Ishida, Hirofumi Sekino, Kenji Fukushima, Hiroshi Ito, Yasuchika Takeishi
Journal: Circulation (2022)

Background: Paravalvular leakage (PVL) is a frequent complication after transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS), and is related to adverse prognosis. We aimed to investigate whether aortic valve calcium volume (Ca-Vol) measured by preoperative cardiac computed tomography (CT) had a predictive value for PVL. Methods and Results: We analyzed consecutive 43 patients underwent TAVI using third-generation self-expandable valve (Evolut PRO ®︎ ) for severe AS with tricuspid valve. Among 43 patients, PVL was detected in 8 cases (18.6%) after TAVI. PVL was defined as moderate or severe regurgitation determined by transthoracic echocardiography. We analyzed preoperative cardiac CT (Fig 1), and measured total Ca-Vol in aortic valve and Ca-Vol in each cusp (non-coronary cusp [NCC], right-coronary cusp [RCC], and left-coronary cusp [LCC]). The threshold of CT value for calcium structure was determined at 500 Hounsfield Units as previously reported. Total Ca-Vol was significantly higher in the PVL group than in the non-PVL group (3.9 ± 2.8 vs. 2.1 ± 1.0 ml, P = 0.004). Ca-Vols in each cusp were also significantly higher in the PVL group than in the non-PVL group (NCC, 1.5 ± 1.0 vs. 0.8 ± 0.4 ml, P = 0.004; RCC, 1.2 ± 1.1 vs. 0.6 ± 0.3 ml, P = 0.007; and LCC, 1.1 ± 0.8 vs. 0.7 ± 0.4 ml, P = 0.021). Univariate logistic regression analysis for PVL indicated that total Ca-Vol and NCC Ca-Vol were predictors for PVL (total Ca-Vol, OR 2.0, 95% CI 1.0-4.1, P = 0.042; NCC Ca-Vol, OR 5.1, 95% CI 1.2-22.2, P = 0.031). By the receiver operating characteristic curve analysis of Ca-Vol for prediction of PVL, the optimal cut off values were 2.3 ml of total Ca-Vol and 0.8 ml of NCC Ca-Vol (Fig 2; AUC = 0.75 and 0.78, sensitivity 0.75 and 0.88, specificity 0.63 and 0.54, respectively). Conclusion: Total Ca-Vol and NCC Ca-Vol were significant predictors for PVL after TAVI. Ca-Vol can be measured routinely with preoperative CT and might be useful in predicting PVL.
Abstract 10208: Troponin Frequency for Diagnosis of NSTEMI Across Estimated Glomerular Filtration Rate: A Nationwide Sample From US Veterans Health Administration
Authors: Shaitalya Vellanki, Gauranga Mahalwar, Gautam R Shroff, Charles A Herzog, Kevin B Lo, Farah Abuazzam, Janani Rangaswami, Roy Mathew
Journal: Circulation (2022)

Introduction: Recent data suggest comparable diagnostic performance of cardiac specific troponin (cTn) in chronic kidney disease (CKD) compared to those without CKD, including when shorter time interval between tests is considered for high sensitivity (hs) assays. Objective: We performed a descriptive analysis of the adherence to recommended testing frequency across CKD stages in a large nationally representative dataset from the US Veterans Health Administration (VHA). Methods: The Loma Linda VA IRB approved the study under expedited review. Unique admissions for non-ST elevation myocardial infarction (NSTEMI) between 1999 and 2022in the VHA system with available cTn lab values (n=104, 390) were evaluated. ANOVA was utilized to compare time between first and second cTn values across CKD groups. After 2012, criteria for cTn interval reduced from 6-9 hours to 3-6 hours for hs-cTn. Criteria were considered met if time interval between cTn checks was &amp;lt; 9 hours before 2012, &amp;lt; 6 h after 2012. All analyses performed using R statistical software. Results: Troponin I was the assay utilized in 80% of the sample; high-sensitivity (hs) assays made up the minority (&amp;lt;1%) and were primarily used after 2012. Average time interval between first and second cTn checks (across all assays over entire observation period) was 8.1, 8.4, 8.5, 9.3, 9.6, 7.9, 8.1 hours for CKD G1, G2, G3a, G3b, G4, G5, ESKD, respectively (p = 0.001, for trend) (Figure). When cardiac catheterization is performed, cTn criteria met was associated with shorter time to cardiac catheterization (48.5h vs. 52.4h, p &lt; 0.001), irrespective of baseline CKD stage. Conclusions: Consistent application of guideline supported practices in NSTEMI care was noted across CKD stages in VHA hospitals, associated with timely diagnostic measures.
Abstract 10419: Mechanical Properties of Flap and Adventitia in Type B Aortic Dissection
Authors: Hai Dong, Minliang Liu, Yumeng Zhou, Arshiya Chhabra, John N Oshinski, Wei Sun, John A Elefteriades, Bradley G Leshnower, Rudolph L Gleason
Journal: Circulation (2022)

Introduction: Type B Aortic Dissection (TBAD) is a lethal disease. The tissue mechanical property is of great importance for estimating TBAD rupture risk. This study sought to characterize the mechanical properties of stiffness and strength of dissection flap and adventitia tissues from patients with chronic TBAD. Methods: Aortic tissue removed from 23 patients undergoing open repair of thoracoabdominal aortic aneurysms secondary to chronic TBAD was analyzed. Uniaxial testing was performed on the flap (circumferential [Circ] n=11, axial n=8) and on the adventitia (Circ n=7, axial n=6 ). The uniaxial lower tangent modulus (uLTM), uniaxial higher tangent modulus (uHTM) and ultimate tensile strength (UTS) were obained for each sample from stress-strain relation (Fig. 1a). We also perfromed biaxial tension testing (BTT, in Circ and Axial) of the flap (n=7) and adventitia (n=9). BTT is closer to the in vivo loading condition than uniaxial testing. Since BTT usually achieves lower maximum stress, here only the biaxial lower tangent modulus (bLTM, Fig. 1b) was obtained. Result: The uLTM of the dissection flap (Fig. 1c), and bLTM of the flap and adventitia (Fig. 1d) in Circ are significantly larger than those in Axial (p=0.006, 0.011, and 0.008, repsectively). In Circ (Fig. 1d), the bLTM of the adventitia is larger than that of the flap (p=0.027). The flap UTS in Circ is larger than that in Axial (Fig. 1f, p&lt;0.001). In Axial, adventitia UTS is larger than flap UTS (Fig. 1f, p=0.001). Conclusions: The adventitia is stiffer and stronger than the dissection flap in patients with cTBAD. These biomechanical data corroborate the surgical axiom of including the adventitia in surgical repair of aortic dissections. Furthermore, the flap and adventitia in Circ are stiffer than those in Axial. These findings may provide insight into the ability of the aorta to maintain its wall integrity in the setting of hypertension and aneurysmal disease, and provide foundations for estimating the risk of TBAD.
Abstract 10292: Factor V Leiden Associated Venous Thromboembolism Risk Declines With Age in the UK Biobank
Authors: Katharine Clapham, Thomas Gilliland, Sara Haidermota, Satoshi Koyama, Pradeep Natarajan
Journal: Circulation (2022)

Introduction: Venous thromboembolism (VTE) is a significant cause of morbidity and mortality. The Factor V Leiden (FVL) variant is a well-described genetic risk factor for VTE. The extent to which FVL exerts influence on VTE risk by age is not well understood. Hypothesis: The VTE risk conferred by the FVL variant is dependent on age. Methods: We utilized a Cox proportional hazards model to calculate the hazard ratio (HR) for incident VTE in individuals in the UK Biobank with one or two alleles of the common FVL variant, rs6025 (chr1:169549811 (GRCh38.p13) C&gt;T) adjusting for age, sex, diabetes mellitus type 2, smoking history, scaled body-mass index, and the first ten principal components. We further examined the relationship of rs6025-related VTE risk with age by performing Cox proportional hazard regression in individuals aged 40-49, 50-59, and 60-69 years. Analyses were conducted in R-4.0. Results: Among 413,722 individuals followed for median of 7 years, 3218 (0.78%) incident VTE events occurred. The presence of the rs6025 variant (allele frequency 0.047) was associated with a 1.7 hazard ratio (HR) of VTE (CI 1.38-2.07, p=2x10 -7 ) overall. However, the relative effects varied by age with hazard ratios for individuals 40-49 years, 50-59 years, and 60-69 years being 2.34 (CI 1.39-3.93, p=0.0014), 1.76 (1.20-2.58, p=0.0035), and 1.5 (CI 1.18-2.01, p=0.0016) ( Figure ). Conclusions: The risk for VTE conferred by the FVL variant appears to decline with age. This finding may help to better identify individuals who would most benefit from FVL screening.
Abstract 10457: Improved 10-Year Cardiovascular Risk Prediction Combining Serum Metabolites With Traditional Cardiovascular Risk Factors in People With Type 2 Diabetes: Edinburgh Type 2 Diabetes Study
Authors: Zhe Huang, Lucija Klaric, Justina Krasauskaite, Wardah Khalid, James F Wilson, Jackie F Price
Journal: Circulation (2022)

Introduction: Cardiovascular disease (CVD) is the leading cause of death for people with type 2 diabetes (T2D). The predictive performance of existing CVD risk scores in T2D populations is suboptimal. Metabolomics is a promising method of identifying novel biomarkers which might improve risk prediction. We aimed to identify a group of metabolites associated with incident CVD in people with T2D and assess its predictive performance over-and-above a current CVD risk score (QRISK3). Methods: In 1,066 individuals with T2D (Edinburgh Type 2 Diabetes Study), a panel of 228 serum metabolites was measured at baseline and incident CVD events were identified over the subsequent 10 years. We applied 100 repeats of Cox LASSO (least absolute shrinkage and selection operator) to select metabolites with frequency &gt;90% as candidate components for a metabolites-based risk score (MRS). The MRS was calculated using the linear predictor in an unpenalized Cox regression model where only candidate metabolites were included. The predictive performance of the MRS was assessed in relation to a reference score which refitted components of QRISK3 plus prevalent CVD and statin use at baseline. Predictive metrics were internally validated using 500-repeat bootstrapping. Results: In 1,021 available individuals (mean age 67.9 years, 51.7% male), 255 people developed CVD (25.0%) during a median of 10.6 years of follow-up. Twelve metabolites relating to fluid balance, ketone bodies, amino acids, fatty acids, glycolysis and lipoproteins were selected to construct the MRS. C-statistics were 0.673 (95%CI 0.642, 0.704) for the MRS alone and 0.718 (95%CI 0.689, 0.747) for the reference score, increasing slightly to 0.736 (95%CI 0.707, 0.764) for the combination of the two. The improved prediction by combining the MRS with the reference score was internally validated in bootstrapping samples, where the C-statistics for the reference score and the combination were 0.679 (95%CI 0.650, 0.708) vs. 0.699 (95%CI 0.671, 0.728) separately. Conclusions: Metabolomics data might improve predictive performance of current CVD risk scores based on traditional risk factors in people with T2D. External validation is warranted to assess the generalizability of improved CVD risk prediction using the MRS.